Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.
Autophagy
Huntington disease
SAFit2
fkbp12.6/fkbp1b
fkbp12/fkbp1a
fkbp51/fkbp5
fkbp52/fkbp4
induced pluripotent stem cells
Journal
Autophagy
ISSN: 1554-8635
Titre abrégé: Autophagy
Pays: United States
ID NLM: 101265188
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
pubmed:
25
5
2021
medline:
8
4
2022
entrez:
24
5
2021
Statut:
ppublish
Résumé
Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Here, we found levels of FKBP5 are significantly reduced in HD R6/2 and zQ175 mouse models and human HD isogenic neural stem cells and medium spiny neurons derived from induced pluripotent stem cells. Moreover, FKBP5 interacts and colocalizes with HTT in the striatum and cortex of zQ175 mice and controls. Importantly, when we decreased FKBP5 levels or activity by genetic or pharmacological approaches, we observed reduced levels of mHTT in our isogenic human HD stem cell model. Decreasing FKBP5 levels by siRNA or pharmacological inhibition increased LC3-II levels and macroautophagic/autophagic flux, suggesting autophagic cellular clearance mechanisms are responsible for mHTT lowering. Unlike rapamycin, the effect of pharmacological inhibition with SAFit2, an inhibitor of FKBP5, is MTOR independent. Further,
Identifiants
pubmed: 34024231
doi: 10.1080/15548627.2021.1904489
pmc: PMC8726715
doi:
Substances chimiques
Huntingtin Protein
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Tacrolimus Binding Proteins
EC 5.2.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4119-4140Subventions
Organisme : NINDS NIH HHS
ID : R01 NS094422
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS100529
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000266
Pays : United States
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